Transplantation offers the promise of life saving and health restoring therapy for hundreds of thousands of patients suffering from end-stage organ failure. Outstanding short-term outcomes have been achieved through the development of multi-drug life-long continuous immunosuppressive regimens. Despite these achievements, significant challenges remain that compromise the long-term outcomes and limit the application of transplantation. Premature graft loss and death remain as stubborn adversaries as evidenced by the inexorable and stagnant graft and patient annual attrition rates that plague our patients. Current thinking holds that CNI-toxicity and donor-specific antibodies are predominant drivers of kidney graft failure, whereas the principle causes of premature death are cardiovascular (CV) disease, infection, and malignancy. Until recently, virtually all transplant regimens relied on calcineurin-inhibitors as their cornerstone immunosuppressive agent. The approval of belatacept, a second generation CD28 pathway inhibitor, provides an alternative which addresses some of the limitations inherent in CNI-based immunosuppression and provides a long-awaited tool in the quest for transplantation tolerance. Belatacept avoids CNI-induced nephrotoxicity, is associated with very low de novo DSA rates, and improves the CV risk profile. Unfortunately, barriers to wide-scale application and improving long-term results persist. As foreshadowed by our early studies in mice and NHP identifying costimulation blockade-resistant rejection, the rates and grades of acute cellular rejection are higher with belatacept than CNI. In addition, infection and immune compromise-related mortality will almost certainly continue because like its predecessors, belatacept-based immunosuppression in its current form is continuous and life-long. Furthermore, humoral rejection is emerging as a major cause of late-graft failure, and adequate non-human primate models to address the problem of B cell alloimmunity are urgently needed. The central goal of our research program and this application is to develop clinically applicable approaches to address near-term needs and ultimately to develop broadly applicable tolerance strategies for use in clinical transplantation. This goal will be accomplished via four interrelated projects and two supporting cores.